1. Field of the Invention
This disclosure relates generally to systems and methods for the delivery of dry powder compositions of therapeutic agents to a patient, and more particularly, to systems, methods, and compositions for the pulmonary delivery of large doses of dry powder compositions of therapeutic agents to a patient in a single application.
2. Description of the Related Art
There are numerous emergency situations where individuals are exposed to one or more toxic agents via inhalation, wherein failure to rapidly provide treatment protocols can lead to debilitating complications and in many cases, death. These situations include not only the exposure of individuals to nuclear, biological, or chemical (NBC) agents in industrial settings, such as when accidents occur in the industrial setting or during chemical transport, but also the exposure of individuals to such agents during warfare or terrorist events. Often, in order to attempt to counter-act the exposure, large doses of drugs must be administered in a rapid manner in order to begin their therapeutic introduction into the patient's systemic circulation. For example, exposure to Sarin, Suman, Tabun, Vx, any number of toxic organophosphates (OPs), or other chemical warfare agents demands the immediate administration of antidote or antidote combination in order to ameliorate the debilitating effects on the battlefield and prevent death. For example, in the event of exposure to Sarin or related, toxic compounds, reversal of nerve agent toxicity depends on the prompt, parenteral administration of the antidotes, such as atropine and pralidoxime (2-PAM-CL), alone or in combination, often in multiple doses over a short period of time.
Although the intravenous (IV) administration of these antidotes has previously and often been preferred, this is not practical in combat situations or civilian mass casualty incidents. In the military, these drugs are typically self-administered intramuscularly (such as in the outer thigh muscle or other large muscle area) with devices such as the Mark I auto-injector, a disposable, spring-loaded and pressure-activated system preloaded with mediation (AtroPen® and ComboPen®). Previous studies have suggested that an intramuscular (IM) injection of 2-PAM-CL (pralidoxime) takes about 2 minutes to reach therapeutic levels in a normovolemic swine model. Peak blood levels of 2-PAM-CL were reached at 8 minutes post-injection. In the instances described herein, time is a critical factor in treatment for nerve agent or toxic chemical exposure, and the reduction in time of delivering a drug to the systemic circulation may save lives.
Inhaled drug delivery is an effective method to introduce drugs into the lungs, pulmonary region, and systemic circulation system of a patient. Inhaled drug delivery is a proven modality for both lung diseases as well as fast acting medicines than cannot be absorbed via the gastro-intestinal tract or when vascular access is not an option due to time limitations or circulatory collapse. The large surface area of the lung is in immediate proximity to the circulating blood supply and can provide a very large permeable surface through which some drugs can quickly pass into the circulating blood.
Deposition into the deep lung (parenchyma distal to the bronchi) has been established to be greatly size dependent. In general, aerosols or particles in the 1-5 μm diameter range will deposit into the distal lung parenchyma were oxygen transport occurs. Dry powder drug particles can be easily and consistently manufactured in the 0.5-5 μm diameter range so that they are suitable for pulmonary delivery and may deposit in the lung parenchyma for systemic or local absorption. This technology exists and is in use for administration of small dose bronchodilators, anti-inflammatories, and insulin.
Nerve agent exposure, toxic chemical exposure, or cardiac collapse are critical situations were it would be advantageous to deliver large dosages of drugs into a patient. Existing emergency drug delivery, when establishment of intravenous access is not an option, is currently performed with an intramuscular auto-injector for NBC exposure or, intraosseous administration (injection or infusion directly into the marrow of a bone, such as the tibia, via a cannula or the equivalent), or endotracheal for the treatment of cardiac arrest. The intramuscular route is relatively slow (2-3 minutes) in delivering protective blood levels of the drug. The intraosseous route has a faster circulatory absorption rate than intramuscular delivery once established but the administration is painful, expensive, requires critical training to use, and is not a realistic option for self administration. In addition, both autoinjector and intraosseous administration require individuals to overcome the anxiety of self injection which may cost valuable time measured in seconds till the drug is administered. Inhaled nebulized liquid or dry powder is particularly useful for delivering bronchodilators for treatment of acute asthmatic symptoms. In this instance, relatively small doses of drugs can be administered via inhalation to effectively and quickly treat broncospasm and restore normal breathing. However, the total drug payload per breath in existing nebulized liquid or dry powder “inhaler” type devices is relatively small.
Existing nebulized liquid has limitations of total drug payload that can be effectively introduced into the inspired air flow. Large volumes of liquefied gas are required to nebulize small quantities of a liquid drug suspension into droplets suitable for pulmonary drug delivery. In this case, most of the inhaled breath volume is the result of the expanded gas from the liquid propellant with very little actual drug volume suspended in that gas volume. The relatively small drug payload per breath would make this system inappropriate for large dosage emergency drug administration, such as in the instance of a person's exposure to a hazardous chemical or other toxic gas agent.
Existing dry powder pulmonary drug delivery technology approaches rely on the active inspiration of the subject to provide enough air velocity over a dry powder reservoir to disperse and suspend the powder from the reservoir into the inspired air flow. In general, the total maximum drug dosage that can be suspended and delivered by these currently existing methods is less than about 0.5 milligram per breath of the patient. Again, the relatively small drug payload per breath would make this system inappropriate for large dosage drug administration in an emergency situation.
This application for patent discloses systems, methods, and therapeutic compositions and formulations for the large-scale, dry powder endotracheal delivery of therapeutic agents to a patient suffering a pulmonary inflammatory response to an external agent.